Diels-alder adducts of benzoxadiazepines and benzothiadiazepines

ABSTRACT

Compounds having the structure ##STR1## and pharmaceutically acceptable salts thereof, wherein Z is oxygen, sulfur or methylene; R 1  is hydrogen, halogen, alkyl, aryl or arylalkyl; R 2  is hydrogen, alkyl, aryl, or arylalkyl; R 3  is hydrogen, alkyl, aryl or arylalkyl; and R 4  is hydrogen, halogen, alkyl, phenyl, dialkylamidosulfonyl or trifluoromethyl, have useful central nervous system activity.

This is a division of application Ser. No. 531,512, filed Dec. 11, 1974,now U.S. Pat. No. 4,003,905.

SUMMARY OF THE INVENTION

Compounds having the structure ##STR2## and the pharmaceuticallyacceptable salts thereof, have useful pharmacological activity. Informula I, and throughout the specification, the symbols are as definedbelow:

Z is oxygen, sulfur or methylene;

R₁ is hydrogen, halogen, alkyl, aryl or arylalkyl;

R₂ is hydrogen, alkyl, aryl or arylalkyl;

R₃ is hydrogen, alkyl, aryl or arylalkyl; and

R₄ is hydrogen, halogen, alkyl, phenyl, dialkylamidosulfonyl ortrifluoromethyl;

With the proviso that when Z is oxygen or sulfur, and R₄ is phenyl ordialkylamidosulfonyl, R₄ must be para to the oxygen or sulfur atom.

The term "alkyl", as used throughout the specification, refers tostraight or branched chain alkyl groups having 1 to 4 carbon atoms.Methyl is the preferred alkyl group.

The term "aryl", as used throughout the specification, refers to phenylor phenyl substitutd with halogen, alkyl or alkoxy. Phenyl is thepreferred aryl group.

The term "halogen", as used throughout the specification, refers tochlorine, fluorine and bromine. Chlorine and bromine are the preferredhalogens.

The term "alkoxy", as used throughout the specification, refers togroups having the formula Y--O-- wherein Y is alkyl as defined above.Methoxy is the preferred alkoxy group.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention have useful central nervous systemstimulant activity in mammalian species, such as rats, dogs, etc., andcan be used in the same manner as dextroamphetamine for the treatment ofdrowsiness or for the supression of appetite.

The compounds of this invention can be administered in a daily dose offrom about 25 milligrams/70 kilograms to 2 grams/70 kilograms,preferably from about 25 milligrams/70 kilograms to 1 gram/70 kilograms.The compounds can be administered orally or parenterally in the form oftablets, capsules, elixirs, injectables or the like by incorporating theappropriate dosage of the compound with carriers according to acceptedpharmaceutical practice.

The compounds of formula I can be prepared from maleimides having thestructure ##STR3## and from tricyclic compounds having the structure##STR4## The N-maleimides of formula II are well known in the art andare readily obtainable by reaction of maleic anhydride and an aminehaving the formula R₃ --NH₂. The compounds of formula III are known:see, U.S. Pat. No. 3,825,549, issued July 23, 1974; U.S. patentapplication Ser. No. 347,938, filed Apr. 4, 1973; and now U.S. Pat. No.3,857,850, issued Dec. 31, 1974 and U.S. patent application Ser. No.347,939, filed Apr. 4, 1973, and now U.S. Pat. No. 3,856,801, issuedDec. 24, 1974.

The reaction of a tricyclic compound of formula III with anN-substituted maleimide of formula II can be carried out in an organicsolvent at elevated temperatures. While the choice of solvent andreaction conditions is not critical, the reaction will most preferablybe run in an aromatic hydrocarbon solvent, such as xylene, under refluxconditions.

The compounds of formula I can be converted into pharmaceuticallyacceptable acid addition salts using procedures well known in the art.Illustrative acid addition salts are the hydrohalides, especially thehydrochloride and hydrobromide which are preferred, sulfate, nitrate,phosphate, tartrate, maleate, fumarate, citrate, succinate,methanesulfonate, toluenesulfonate, benzenesulfonate and the like.

The compounds of formula I wherein R₁ and R₂ are hydrogen are preferred.

The compounds of formula I wherein R₁, R₂ and R₄ are hydrogen arepreferred.

The following examples are specific embodiments of this invention.

EXAMPLE 13a,4,13,13a-Tetrahydro-2-methyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzothiadiazepine-1,3(2H)-dione

A solution of 6H-pyrido [1,2c][1,3,5]benzothiadiazepine (0.8 g) andN-methylmaleimide (0.6 g) in 30 ml of xylene is heated under reflux withstirring for 16 hours. The reaction mixture is allowed to cool and 1.03g of solid crude product is collected and washed with xylene. The crudematerial is recrystallized from 200 ml of toluene to give 0.6 g of thetitle compound, melting point 285°-287° C, dec.

EXAMPLE 23a,4,10,11,13,13a-Hexahydro-2-methyl-4,13-etheno-1H-pyrrolo[3',4':4,5]pyrido[2,1-b][1,3]benzodiazepine-1,3(2H)-dione

A solution of 11,12-dihydropyrido [2,1-b][1,3]benzodiazepine (1.96 g)and N-methylmaleimide (1.68 g) in 50 ml of xylene is heated under refluxconditions for 23 hours. The reaction mixture is allowed to cool to roomtemperature and then placed in a refrigerator for about 16 hours. Theproduct is isolated and dried to give 3.07 g of material.Recrystallization of the material from 50 ml of toluene gives 2.04 g ofthe title compound, which after drying in vacuo at 110° C for 6 hours,has a melting point of 215°-217° C.

EXAMPLE 310-Chloro-3a,4,13,13a-tetrahydro-2-methyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c]-[1,3,5]benzoxadiazepine-1,3(2H)-dione

A solution of 2-chloro-6H-pyrido[1,2-c][1,3,5]benzoxadiazepine (0.58 g)and N-methylmaleimide (0.41 g) in 30 ml of xylene is heated under refluxconditions for 6 days. The solution is filtered while still hot andallowed to cool to room temperature. The crystalline material thatseparates is collected, washed with xylene and dried to give 0.6 g ofthe title compound, sintering at 240° C and having a melting point250°-251° C.

EXAMPLE 4

3a,4,13,13a-Tetrahydro-2-phenyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)-dione

A mixture of 6H-pyrido[1,2-c][1,3,5]benzoxadiazepine (1.98 g) andN-phenylmaleimide (2.07 g) in 80 ml of xylene is heated under refluxconditions for 21 hours. After cooling to room temperature, the mixtureis allowed to stand in a refrigerator for about 16 hours. The crudeproduct is then collected and recrystallized from 250 ml of toluene. Thematerial is filtered, suspended in hexane and filtered again. Drying invacuo at 110° C for 6 hours gives 1.56 g of the title compound, meltingpoint 243°-244° C.

EXAMPLE 53a,4,13,13a-Tetrahydro-2-methyl-4,13-ethano-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]-benzoxadiazepine-1,3(2H)-dione

A mixture of 6H-pyrido[1,2-c][1,3,5]benzoxadiazepine (1.98 g) andN-methylmaleimide (1.68 g) in 50 ml of xylene is heated under refluxconditions for 23 hours. The reaction mixture is allowed to cool to roomtemperature and then allowed to stand in a refrigerator for 5 hours. Thecrude product is collected, washed with xylene and dried in vacuo forabout 16 hours at room temperature and for 6 hours at 110° C to give2.43 g of the title compound, melting point 252°-253° C.

EXAMPLES 6 to 13

Following the procedure of Example 1, but substituting thebenzothiadiazepine listed in column I for6H-pyrido-[1,2-c][1,3,5]benzothiadiazepine and the N-substitutedmaleimide listed in column II for N-methylmaleimide, the compound listedin column III is obtained.

      Example Column I Column II Column III           6      ##STR5##      ##STR6##      ##STR7##      7      ##STR8##      ##STR9##      ##STR10##      8      ##STR11##      ##STR12##      ##STR13##      9      ##STR14##      ##STR15##      ##STR16##      10      ##STR17##      ##STR18##      ##STR19##      11      ##STR20##      ##STR21##      ##STR22##      12      ##STR23##      ##STR24##      ##STR25##      13      ##STR26##      ##STR27##      ##STR28##

EXAMPLES 14 - 20

Following the procedure of Example 2, but substituting thebenzodiazepine listed in column I for11,12-dihydropyrido[2,1-b][1,3]benzodiazepine and the N-substitutedmaleimide for N-methylmaleimide listed in column II, the compound listedin column III is obtained.

      Example Column I Column II Column III           14      ##STR29##      ##STR30##      ##STR31##      15      ##STR32##      ##STR33##      ##STR34##      16      ##STR35##      ##STR36##      ##STR37##      17      ##STR38##      ##STR39##      ##STR40##      18      ##STR41##      ##STR42##      ##STR43##      19     ##STR44##      ##STR45##      ##STR46##      20     ##STR47##      ##STR48##      ##STR49##

EXAMPLES 21-29

Following the procedure of Example 3, but substituting thebenzoxadiazepin e listed in column I for2-chloro-6H-pyrido[1,2-c][1,3,5]benzoxadiazepine and the N-substitutedmaleimide listed in column II for N-methylmaleimid e, the compoundlisted in column III is obtained.

      Example Column I Column II Column III           21      ##STR50##      ##STR51##      ##STR52##      22     ##STR53##      ##STR54##      ##STR55##      23     ##STR56##      ##STR57##      ##STR58##      24     ##STR59##      ##STR60##      ##STR61##      25     ##STR62##      ##STR63##      ##STR64##      26     ##STR65##      ##STR66##      ##STR67##      27     ##STR68##      ##STR69##      ##STR70##      28     ##STR71##      ##STR72##      ##STR73##      29     ##STR74##      ##STR75##      ##STR76##

EXAMPLE 30 10-Chloro-3a,4,13,13a-tetrahydro-2-methyl-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)dione, hydrochloride

To 3.40 g of10-chloro-3a,4,13,13a-tetrahydro-2-methyl-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)dione in 25 ml of drychloroform is added, dropwise, and with external wet ice cooling, 10.0ml of a 1.05 N ethereal hydrogen chloride solution to obtain the titlecompound.

What is claimed is:
 1. A compound having the structure ##STR77## or apharmaceutically acceptable salt thereof, wherein Z is oxygen or sulfur;R₁ is hydrogen, halogen, alkyl, aryl or arylalkyl; R₂ is hydrogen,alkyl, or arylalkyl; l; R₃ is hydrogen, alkyl, aryl or arylalkyl; and R₄is hydrogen, halogen, alkyl phenyl, dialkylamidosulfonyl ortrifluoromethyl; with the proviso that when R₄ is phenyl ordialkylamidosulfonyl, R₄ must be para to the oxygen or sulfur atom; andwherein alkyl and alkoxy refer to groups having 1 to 4 carbon atoms andaryl refers to phenyl or phenyl substituted with halogen, alkyl oralkoxy.
 2. A compound in accordance with claim 1 having the structure##STR78##
 3. A compound in accordance with claim 1 having the structure##STR79##
 4. A compound in accordance with claim 1 wherein R₁ and R₂ arehydrogen.
 5. A compound in accordance with claim 1 wherein R₃ ishydrogen.
 6. A compound in accordance with claim 1 wherein R₃ is alkyl.7. A compound in accordance with claim 1 wherein R₃ is aryl.
 8. Acompound in accordance with claim 1 wherein R₃ is arylalkyl.
 9. Thecompound in accordance with claim 1 having the name3a,4,13,13a-tetrahydro-2-methyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzothiadiazepine-1,3(2H)-dione.
 10. Thecompound in accordance with claim 1 having the name3a,4,13,13a-tetrahydro-2-phenyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)-dione.
 11. Thecompound in accordance with claim 1 having the name3a,4,13,13a-tetrahydro-2-methyl-4,13-etheno-1H,6H-pyrrolo[3',4':4,5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)-dione.12. The compound in accordance with claim 1 having the name10-chloro-3a,4,13,13a-tetrahydro-2-methyl-4,13-etheno-1H,6H-pyrrolo[3',4':4.5]pyrido[1,2-c][1,3,5]benzoxadiazepine-1,3(2H)-dione.